Naturally occurring glucokinase mutations are associated with defects in posttranslational S-nitrosylation.

Molecular Endocrinology
Shi-Ying DingMark A Rizzo

Abstract

Posttranslational activation of glucokinase (GCK) through S-nitrosylation has been recently observed in the insulin-secreting pancreatic beta-cell; however, the function of this molecular mechanism in regulating the physiology of insulin secretion is not well understood. To more fully understand the function of posttranslational regulation of GCK, we examined two naturally occurring GCK mutations that map to residues proximal to the S-nitrosylated cysteine and cause mild fasting hyperglycemia (maturity-onset diabetes of the young; subtype glucokinase). The kinetics of recombinantly generated GCK-R369P and GCK-V367M were assessed in vitro. The GCK-R369P protein has greatly reduced catalytic activity (relative activity index 0.05 vs. 1.00 for wild type), whereas the GCK-V367M has near normal kinetics (relative activity index 1.26 vs. 1.00 for wild type). Quantitative imaging and biochemical assays were used to assess the effect of these mutants on the metabolic response to glucose, GCK activation, and S-nitrosylation of GCK in betaTC3 insulinoma cells. Expression of either mutant in betaTC3 cells did not affect the metabolic response to 5 mM glucose. However, expression of either mutant blocked the effects of insulin on glucose-s...Continue Reading

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Citations

Mar 1, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Puneet Anand, Jonathan S Stamler
Nov 26, 2010·Human Genetics·Yunfeng ShenJianping Weng
Jul 13, 2011·Biochimica Et Biophysica Acta·Nadzeya V Marozkina, Benjamin Gaston
Jul 24, 2012·Biochimica Et Biophysica Acta·Maria NegahdarLise Bjørkhaug
Nov 29, 2013·Journal of Pharmacological Sciences·Yukiko Kurohane Kaneko, Tomohisa Ishikawa
Oct 11, 2016·Nitric Oxide : Biology and Chemistry·Sarah L Wynia-Smith, Brian C Smith
Feb 27, 2015·World Journal of Biological Chemistry·Ji Yeon KimWon-Ho Kim
Apr 2, 2011·The Journal of Biological Chemistry·Shi-Ying DingMegan A Rizzo
May 11, 2018·Antioxidants & Redox Signaling·Petr Heneberg
Dec 25, 2015·The Journal of Biological Chemistry·Michele L MarkwardtMegan A Rizzo

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